A method for synthesizing n-substituted tropinone derivatives

Abstract

This invention provides a method for synthesizing N-substituted tropinone derivatives, relating to the field of organic synthesis technology. The method involves reacting a tropinone compound with a fatty amine derivative in a solvent environment under the action of an acid promoter to generate an N-substituted tropinone derivative in one step. This method can synthesize N-substituted tropinone derivatives in one step, which is greener and more efficient than the two-step method of first reacting tropinone with the highly toxic reagent iodomethane to generate a quaternary ammonium salt intermediate, and then reacting it with a fatty amine derivative under alkaline conditions. Furthermore, the raw materials used are inexpensive and readily available, the reaction conditions are milder, making it more suitable for large-scale production, possessing potential industrial value, and showing broad application prospects.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing N-substituted tropine derivatives. Background Technology

[0002] Tropinone, with the chemical formula C8H 13 No, as a representative of tropine derivatives, tropine is used as a pharmaceutical intermediate in the synthesis of many important drugs. For example, tropine can be further converted into other alkaloids, such as cocaine, which is a tropine alkaloid and belongs to the N-substituted tropine derivatives. Tropine derivatives have wide applications in pharmaceuticals, pesticides, and other fields. In recent years, with the deepening of research on the biosynthesis of natural products, the synthetic routes of tropine and its derivatives have been continuously optimized, providing more possibilities for new drug development. Literature indicates that when there is a substituent at the N position of the 8th position of the hyoscyamine skeleton, it can enhance the affinity for D2 and 5-HT2A receptors and have stronger biological activity (Reference: Stefanowicz, J., Słowiński, T., Wróbel, MZ, Herold, F., Gomółka, AE, Wesołowska, A., & Turło, J. Synthesis and biological investigation of new equatorial (β) stereoisomers of 3-aminotropane arylamides with atypical antipsychotic profile. Bioorganic & Medicinal Chemistry, 2016, 24(18): 3994-4007.). Therefore, group modification at the N position of the 8th position has potential pharmaceutical value and may open up new directions for the development of novel drugs.

[0003] Currently, the synthesis of N-substituted tropinone derivatives typically requires two or more steps. For example, Nicolas Willand et al. reported a two-step synthesis of N-substituted tropinone derivatives by first reacting tropinone with iodomethane to generate a quaternary ammonium salt intermediate, and then reacting it with an aliphatic amine derivative under alkaline conditions (Reference: Willand, N., Folléas, B., Bouutillon, C., Verbraeken, L., Gesquière, JC, Tartar, A., & Deprez, B. Efficient, two-step synthesis of N-substituted nortropinone derivatives. Tetrahedron Letters, 2007, 48(29): 5007-5011.), and this method requires the use of the highly toxic substance iodomethane. Nicolaou et al. reported the synthesis of 8-azabicyclo[3.2.1]octane skeleton using cycloheptanol as a starting material (Reference: Nicolaou, KC, Montagnon, T., Baran, PS, & Zhong, YL Iodine (V) reagents in organic synthesis. Part 4. o-Iodoxybenzoic acid as a chemospecific tool for single electrontransfer-based oxidation processes. Journal of the American Chemical Society, 2002, 124(10): 2245-2258.). However, the IBX oxidant used in the synthesis process severely limits the diversity of substrates involved, and this oxidant is hazardous and belongs to the category of explosive reagents.Huang et al. reported a three-step reaction of intramolecular cyclization of ketone-lactams to construct N-substituted tropane derivatives (Reference: Su-Yu Huang, Zong Chang, Shi-Chuan Tuo, Long-Hui Gao, Ai-E Wang and Pei-Qiang Huang. Versatile construction of functionalized tropane ring systems based on lactam activation: enantioselective synthesis of (+)-pervilleine B. Chemical Communications., 2013, 49(63): 7088-7090.). This method requires three steps to obtain the target product, and the obtained product contains a mixture of enantiomers.

[0004] In conclusion, there is an urgent need to develop a greener, simpler, and more efficient method for synthesizing N-substituted tropidine derivatives. Summary of the Invention

[0005] The purpose of this invention is to provide a method for synthesizing N-substituted tropinone derivatives. In a solvent environment with the aid of an acid accelerator, tropinone compounds react with aliphatic amine derivatives to generate N-substituted tropinone derivatives in a single step. This invention solves the problems of cumbersome reaction steps, highly toxic catalysts, and hazardous reactions in existing technologies. The synthetic method provided by this invention reduces the reaction steps from the usual two or three steps to a single step for the synthesis of N-substituted tropinone derivatives. Furthermore, the reaction conditions are mild, the operation is simple, and the reactant tropinone compounds are inexpensive and readily available, resulting in low economic costs. In addition, this invention's synthetic method does not use precious metals, reducing heavy metal pollution, and no toxic gases or liquids are generated during the reaction, thus better meeting the requirements of green chemistry.

[0006] This invention provides a method for synthesizing N-substituted tropinone derivatives, comprising: in a solvent environment, under the action of an acid promoter, reacting tropinone compound I with aliphatic amine derivative II to generate N-substituted tropinone derivative III in one step, wherein the reaction temperature is 70℃-90℃;

[0007] ;

[0008] Where m is independently selected from natural numbers 1-3, and R 1 C4-C 60 Substituted or unsubstituted aryl groups, sulfur- or oxygen-containing five-membered aromatic heterocycles, pyridine groups, or aliphatic cycloalkyl groups;

[0009] The aliphatic amine derivative II is one of the following: benzylamine derivative, primary amine derivative containing a thiophene ring, primary amine derivative containing a furan ring, primary amine derivative containing a pyridine ring, primary amine derivative containing an aliphatic chain, or primary amine derivative containing an aliphatic ring.

[0010] Optionally, the solvent includes at least one selected from ethanol, toluene, DMF, DME, DMSO, acetonitrile, and ethylene glycol.

[0011] Optionally, the acid promoter includes at least one of TsOH, benzoic acid, p-nitrobenzoic acid, HCl, H2SO4, and trifluoromethanesulfonic acid.

[0012] Optionally, the molar ratio of the acid promoter to tropinone compound I is (1-2):1.

[0013] Optionally, the molar ratio of the fatty amine derivative II to the tropinone compound I is (1-2):1.

[0014] Optionally, the solvent dosage is 1 mL to 5 mL of solvent per 0.5 mmol of tropinone compound.

[0015] Optionally, the reaction lasts for 8-12 hours.

[0016] Optionally, the reaction may generate N-substituted pyrrole ring compounds as byproducts, as shown in Formula IV:

[0017] .

[0018] Optionally, the structure of the above benzylamine derivative is shown in Formula II-1:

[0019] ;

[0020] Among them, R 2 For C1-C 40 The substituted or unsubstituted aliphatic, alkoxy, cyano, or trifluoromethyl groups.

[0021] Optionally, the structures of the above-mentioned primary amine derivatives containing thiophene rings, primary amine derivatives containing furan rings, and primary amine derivatives containing pyridine rings are shown in Formula II-2, Formula II-3, and Formula II-4, respectively:

[0022] , , ;

[0023] Among them, R 3 Hydrogen, C1-C 40 The substituted or unsubstituted aliphatic, alkoxy, cyano, trifluoromethyl or halogen groups.

[0024] Optionally, the structure of the above-mentioned primary amine derivatives containing aliphatic chains is shown in Formula II-5:

[0025] ;

[0026] Where n1 is selected from natural numbers 1-59.

[0027] Optionally, the structure of the above-mentioned primary amine derivative containing an aliphatic ring is shown in formula II-6:

[0028] ;

[0029] Where n2 is selected from natural numbers from 1 to 15.

[0030] The beneficial effects of this invention are as follows:

[0031] (1) The method of this invention synthesizes N-substituted tropinone derivatives in one step, greatly simplifying the synthetic route and making the operation simple. Economically, the method of this invention uses tropinone compounds as reactants, which are inexpensive and readily available, reducing economic costs. Environmentally, it avoids the use of precious metals, and the reaction conditions are mild, with no toxic gases or liquids generated during the reaction, which is more in line with the requirements of green chemistry. The method of this invention is suitable for large-scale preparation and has potential industrial value.

[0032] (2) The method of the present invention has good functional group compatibility and a wide range of applicable substrates. In addition, the convenient one-step synthesis route provides new possibilities for the construction of N-substituted tropidine derivatives and the development of new drugs, thereby providing support for accelerating drug screening. It has practical application value in the fields of drug development and functional materials and has broad application prospects. Attached Figure Description

[0033] Figure 1 The reaction equation for the formation of N-substituted tropinone derivative III from tropinone compound I and fatty amine derivative II;

[0034] Figure 2 The 1H NMR spectrum of 8-benzyl-8-azabicyclo[3.2.1]octane-3-one prepared in Example 1 of this invention;

[0035] Figure 3 The carbon NMR spectrum of 8-benzyl-8-azabicyclo[3.2.1]octane-3-one prepared in Example 1 of this invention;

[0036] Figure 4 The 1H NMR spectrum of N-benzylpyrrole prepared from the byproduct of Example 1 of this invention;

[0037] Figure 5 The carbon NMR spectrum of N-benzylpyrrole prepared from the byproduct of Example 1 of this invention;

[0038] Figure 6 The 1H NMR spectrum of 8-(4-methylbenzyl)-8-azabicyclo[3.2.1]octane-3-one prepared in Example 2 of this invention;

[0039] Figure 7 The carbon NMR spectrum of 8-(4-methylbenzyl)-8-azabicyclo[3.2.1]octane-3-one prepared in Example 2 of this invention;

[0040] Figure 8 The 1H NMR spectrum of N-(4-methylbenzyl)pyrrole prepared as a byproduct of Example 2 of this invention;

[0041] Figure 9 The carbon NMR spectrum of N-(4-methylbenzyl)pyrrole prepared as a byproduct of Example 2 of this invention;

[0042] Figure 10 The 1H NMR spectrum of 8-(2-bromo-5-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-one prepared in Example 3 of this invention;

[0043] Figure 11 The carbon NMR spectrum of 8-(2-bromo-5-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-one prepared in Example 3 of this invention;

[0044] Figure 12 The 1H NMR spectrum of N-(2-bromo-5-fluorobenzyl)pyrrole prepared from the byproduct of Example 3 of this invention;

[0045] Figure 13 The carbon NMR spectrum of N-(2-bromo-5-fluorobenzyl)pyrrole prepared from the byproduct of Example 3 of this invention;

[0046] Figure 14 The 1H NMR spectrum of 8-(benzo[d][3,4]dioxonylbenzyl)-8-azabicyclo[3.2.1]octane-3-one prepared in Example 4 of this invention;

[0047] Figure 15 The carbon NMR spectrum of 8-(benzo[d][3,4]dioxonylbenzyl)-8-azabicyclo[3.2.1]octane-3-one prepared in Example 4 of this invention;

[0048] Figure 16 The 1H NMR spectrum of N-(benzo[d][3,4]dioxonylbenzyl)pyrrole prepared as a byproduct of Example 4 of this invention;

[0049] Figure 17 The carbon NMR spectrum of N-(benzo[d][3,4]dioxonylbenzyl)pyrrole prepared as a byproduct of Example 4 of this invention;

[0050] Figure 18 The 1H NMR spectrum of 8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-one prepared in Example 5 of this invention;

[0051] Figure 19 The carbon NMR spectrum of 8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-one prepared in Example 5 of this invention;

[0052] Figure 20 The 1H NMR spectrum of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one prepared in Example 6 of this invention;

[0053] Figure 21 The carbon NMR spectrum of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one prepared in Example 6 of this invention. Detailed Implementation

[0054] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise defined, the technical or scientific terms used herein should have the ordinary meaning understood by those skilled in the art to which this invention pertains.

[0055] This invention provides a method for synthesizing N-substituted tropinone derivatives, comprising: in a solvent environment, under the action of an acid promoter, reacting tropinone compound I with a fatty amine derivative II to generate N-substituted tropinone derivative III in one step, wherein the reaction temperature is 70℃-90℃; the reaction formula is as follows or see below. Figure 1 :

[0056] ;

[0057] Where m is independently selected from natural numbers 1-3, and R 1 C4-C 60 Substituted or unsubstituted aryl groups, sulfur- or oxygen-containing five-membered aromatic heterocycles, pyridine groups, or aliphatic cycloalkyl groups;

[0058] The aliphatic amine derivative II is one of the following: benzylamine derivative, primary amine derivative containing a thiophene ring, primary amine derivative containing a furan ring, primary amine derivative containing a pyridine ring, primary amine derivative containing an aliphatic chain, or primary amine derivative containing an aliphatic ring.

[0059] In fact, in the reaction system, tropinone compounds react directly with aliphatic amine derivatives, causing the tropinone compounds to be demethylated under acidic conditions, thereby generating diene intermediates. These intermediates react with primary amine derivative II to generate N-substituted tropinone derivatives. In some examples, byproducts of N-substituted pyrrole ring compounds are generated, presumably from the removal of one molecule of acetone from the N-substituted tropinone derivatives.

[0060] In fact, the synthesis method provided by this invention is applicable to different R... 1 The fatty amine derivatives of the group have good applicability and can generate N-substituted tropidine derivatives with different structures, which is beneficial for their application in the synthesis of drugs and pharmaceutical intermediates.

[0061] In some embodiments, the solvent includes at least one selected from ethanol, toluene, DMF, DME, DMSO, acetonitrile, and ethylene glycol. In practice, the solvent does not participate in the reaction, but it dissolves the reactants, providing a uniform and controllable liquid environment to ensure the reaction proceeds.

[0062] In some embodiments, the acid promoter includes at least one of TsOH, benzoic acid, p-nitrobenzoic acid, HCl, H2SO4, and trifluoromethanesulfonic acid. In fact, the acid acts as a promoter, and under the action of the acid promoter, tropidine can generate diene intermediates.

[0063] In some embodiments, the molar ratio of the acid promoter to tropinone compound I is (1-2):1.

[0064] In some embodiments, the molar ratio of fatty amine derivative II to tropinone compound I is (1-2):1.

[0065] In some embodiments, the solvent dosage is 1-5 mL of solvent added for every 0.5 mmol of tropidine compound.

[0066] In some embodiments, the reaction temperature is 70°C-90°C. In practice, an oil bath is usually used for heating during the reaction.

[0067] In some embodiments, the reaction lasts for 8-10 hours.

[0068] In fact, the method of the present invention has mild reaction conditions. When the reaction system is heated and refluxed, the reaction can be carried out directly in an air atmosphere. When the reactants are different, it is necessary to adjust the input ratio of the reactants, the reaction temperature and the reaction time appropriately to promote the reaction and ensure the reaction process and efficiency.

[0069] In some embodiments, the synthesis reaction may produce byproduct N-substituted pyrrole ring compounds as shown in Formula IV:

[0070] .

[0071] In fact, the formation of N-substituted pyrrole ring compounds as byproducts during the reaction process is one of the reasons for the low yield of N-substituted tropinone derivatives. In fact, N-substituted pyrrole ring compounds are also the core pharmacodynamic structure or key components of many medical drugs, and this byproduct also has application value.

[0072] In some embodiments, the structure of the benzylamine derivative is shown in Formula II-1:

[0073] ;

[0074] Among them, R 2 For C1-C 40 The substituted or unsubstituted aliphatic, alkoxy, cyano, or trifluoromethyl groups;

[0075] Specifically, when the benzylamine derivative shown in formula II-1 reacts with tropinone compound I to generate the N-substituted tropinone derivative shown in formula III-1, the reaction formula is as follows:

[0076] .

[0077] In some embodiments, the structures of the primary amine derivatives containing thiophene rings, primary amine derivatives containing furan rings, and primary amine derivatives containing pyridine rings are shown in Formula II-2, Formula II-3, and Formula II-4, respectively:

[0078] , , ;

[0079] Among them, R 3 Hydrogen, C1-C 40 Substituted or unsubstituted aliphatic, alkoxy, cyano, trifluoromethyl, or halogen groups;

[0080] Specifically, when the primary amine derivative containing a thiophene ring shown in formula II-2 reacts with tropidine compound I to generate the N-substituted tropidine derivative shown in formula III-2, the reaction formula is as follows:

[0081] ;

[0082] When the primary amine derivative containing a furan ring shown in formula II-3 reacts with tropidine compound I to generate the N-substituted tropidine derivative shown in formula III-3, the reaction formula is as follows:

[0083] ;

[0084] When the primary amine derivative containing a pyridine ring shown in formula II-4 reacts with tropidine compound I to generate the N-substituted tropidine derivative shown in formula III-4, the reaction formula is as follows:

[0085] .

[0086] In some embodiments, the reactants contain the structure of aliphatic primary amine derivatives as shown in Formula II-5:

[0087] ;

[0088] Where n1 is selected from natural numbers 1-59;

[0089] Specifically, when the primary amine derivative containing an aliphatic chain shown in formula II-5 reacts with tropinone compound I to generate the N-substituted tropinone derivative shown in formula III-5, the reaction formula is as follows:

[0090] ;

[0091] In some embodiments, the reactants contain the structure of aliphatic primary amine derivatives as shown in formula II-6:

[0092] ;

[0093] Where n2 is selected from natural numbers 1-15;

[0094] Specifically, when the primary amine derivative containing an aliphatic chain shown in formula II-6 reacts with tropinone compound I to generate the N-substituted tropinone derivative shown in formula III-6, the reaction formula is as follows:

[0095] .

[0096] In fact, the aliphatic groups in any of the above structural formulas are independently either alicyclic groups or aliphatic alkyl groups. Specifically, C1-C 40 The aliphatic groups include methyl, tert-butyl, propyl, isopropyl, and butyl, and the halogens include F, Cl, Br, and I.

[0097] In fact, after the reaction was completed, water was added to quench the reaction system, followed by extraction with an organic solvent. The organic phase was dried with anhydrous Na2SO4 to remove the organic solvent, and pure N-substituted tropidine was obtained by column chromatography.

[0098] The characterization instruments used in the following specific embodiments are superconducting nuclear magnetic resonance spectrometers manufactured by Agilent Technologies, Inc., USA, models: 400MR DD2 and 600MR DD2.

[0099] Example 1

[0100] Example 1 provides a method for synthesizing 8-benzyl-8-azabicyclo[3.2.1]octane-3-one, comprising: adding 0.5 mmol tropine and 114 mg (0.6 mmol) TsOH to a dry Schlenk reaction tube, then adding 2.0 mL of 95% ethanol to the dry Schlenk reaction tube, and finally adding 65 mg (0.5 mmol) benzylamine. After mixing, the mixture is heated under air atmosphere and refluxed in an oil bath at 80°C for 10 h, after which the reaction is stopped. After the reaction is completed, water is added to quench the reaction system, and then ethyl acetate is used for extraction and separation of the organic phase. The organic phase is dried with anhydrous Na2SO4 to remove the organic solvent, and then purified by column chromatography (silica gel column, eluent is petroleum ether and ethyl acetate in a volume ratio of 5:1) to obtain 51.7 mg of pure 8-benzyl-8-azabicyclo[3.2.1]octane-3-one as a yellow oily liquid, with a calculated yield of 48%; 25.2 mg of the product was obtained. mg of pale yellow oily liquid byproduct N-benzylpyrrole, calculated yield 32%.

[0101] After characterizing the 8-benzyl-8-azabicyclo[3.2.1]octane-3-one prepared in Example 1 by 1H NMR and 1C NMR, the results are as follows: Figure 2 and Figure 3 As shown; and the byproduct N-benzylpyrrole was characterized by 1H NMR and 1C NMR spectra, respectively, as shown in the figures. Figure 4 and Figure 5 As shown.

[0102] The structural formula of the target product, 8-benzyl-8-azabicyclo[3.2.1]octane-3-one:

[0103] ;

[0104] Its NMR characterization data: 1 H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.25 (t, J = 6.8 Hz, 1H), 3.73 (s, 2H), 3.47 (s,2H), 2.72 – 2.61 (m, 2H), 2.18 (d, J = 15.8 Hz, 2H), 2.13 – 2.01 (m, 2H), 1.61 (d, J = 8.2 Hz, 2H); 13 C NMR (101 MHz, CDCl3) δ 210.4, 139.2, 128.4, 128.3, 127.1, 58.5, 55.1, 48.2, 27.8.

[0105] The structural formula of the byproduct N-benzylpyrrole is as follows:

[0106] ;

[0107] Its NMR characterization data: 1 H NMR (600 MHz, CDCl3) δ 7.39 (t, J = 7.9 Hz, 2H), 7.34 (t, J = 7.9 Hz, 1H), 7.18 (d, J = 7.7 Hz, 2H), 6.76 (t, J = 2.1 Hz, 2H), 6.27 (t, J = 2.1 Hz, 2H), 5.12 (s, 2H); 13 C NMR (151 MHz, CDCl3) δ 138.1, 128.6, 127.6, 126.9, 121.1, 108.4, 53.2.

[0108] Example 2

[0109] Example 2 provides a method for synthesizing 8-(4-methylbenzyl)-8-azabicyclo[3.2.1]octane-3-one, comprising: adding 0.5 mmol tropinone and 114 mg (0.6 mmol) TsOH to a dry Schlenk reaction tube, then adding 2.0 mL of 95% ethanol to the dry Schlenk reaction tube, and finally adding 73 mg (0.5 mmol) p-methylbenzylamine. After mixing, the mixture is refluxed in an oil bath at 80°C for 10 minutes under an air atmosphere. The reaction was stopped after h; after the reaction was completed, water was added to the reaction system to quench it, and the organic phase was extracted and separated by ethyl acetate. The organic phase was dried with Na2SO4 to remove the organic solvent, and then purified by column chromatography (silica gel column, eluent was petroleum ether and ethyl acetate in a volume ratio of 5:1) to obtain 51.6 mg of pure 8-(4-methylbenzyl)-8-azabicyclo[3.2.1]octane-3-one as a yellow oily liquid, with a calculated yield of 45%; 24.0 mg of brown oily liquid byproduct N-(4-methylbenzyl)pyrrole was obtained, with a calculated yield of 28%.

[0110] After characterizing the 8-(4-methylbenzyl)-8-azabicyclo[3.2.1]octane-3-one prepared in Example 2 by 1H NMR and 1C NMR, the results are as follows: Figure 6 and Figure 7 As shown; and the byproduct N-(4-methylbenzyl)pyrrole was characterized by 1H NMR and 1C NMR spectra, respectively, as shown in the figures. Figure 8 and Figure 9 As shown.

[0111] The structural formula of 8-(4-methylbenzyl)-8-azabicyclo[3.2.1]octane-3-one:

[0112] ;

[0113] Its NMR characterization data: 1 H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 7.4 Hz, 2H), 7.13 (d, J = 7.3 Hz, 2H), 3.68 (s, 2H), 3.46 (s, 2H), 2.65 (d, J = 15.8 Hz, 2H), 2.33 (s, 3H), 2.17 (d, J = 15.8 Hz, 2H), 2.11 – 2.04 (m, 2H), 1.59 (d, J= 8.2 Hz, 2H); 13 C NMR (101 MHz, CDCl3) δ 210.3, 136.6, 136.1, 128.9, 128.3, 58.3, 54.7, 48.1, 27.7, 21.0.

[0114] The structural formula of the byproduct N-(4-methylbenzyl)pyrrole:

[0115] ;

[0116] Its NMR characterization data: 1 H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 7.9 Hz, 2H), 7.04 (d, J = 7.9 Hz, 2H), 6.70 (t, J = 2.0 Hz, 2H), 6.20 (t, J = 2.0 Hz, 2H), 5.04 (s, 2H), 2.35 (s, 3H); 13 C NMR (151 MHz, CDCl3) δ 137.4, 135.1, 129.4, 127.1, 121.1, 108.4, 53.1, 21.1.

[0117] Example 3

[0118] Example 3 provides a method for synthesizing 8-(2-bromo-5-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-one, comprising: adding 0.5 mmol tropinone and 114 mg (0.6 mmol) TsOH to a dry Schlenk reaction tube, then adding 2.0 mL of 95% ethanol to the dry Schlenk reaction tube, and finally adding 103 mg (0.5 mmol) 2-bromo-5-fluorobenzylamine. After mixing, the mixture is heated under reflux in an oil bath at 80°C for 10 h in air, and then the reaction is stopped. After the reaction is completed, the reaction system is quenched with water, and the organic phase is extracted with ethyl acetate and separated. The organic phase is dried with Na2SO4 to remove the organic solvent, and then purified by column chromatography (silica gel column, eluent is petroleum ether and ethyl acetate in a volume ratio of 5:1) to obtain 52.5 mg of pure 8-(2-bromo-5-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-one in brown oily liquid, calculated yield 34%; 48.1 mg of N-(2-bromo-5-fluorobenzyl)pyrrole in orange oily liquid byproduct, calculated yield 38%.

[0119] After characterizing the 8-(2-bromo-5-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-one prepared in Example 3 by 1H NMR and 1C NMR, the results are as follows: Figure 10 and Figure 11 As shown; and the byproduct N-(2-bromo-5-fluorobenzyl)pyrrole was characterized by 1H NMR and 1C NMR spectra, respectively, as shown in the figures. Figure 12 and Figure 13 As shown.

[0120] The structural formula of 8-(2-bromo-5-fluorobenzyl)-8-azabicyclo[3.2.1]octane-3-one:

[0121] ;

[0122] Its NMR characterization data: 1 H NMR (400 MHz, CDCl3) δ 7.48-7.42 (m, 2H), 6.85 (td,J = 8.3, 3.1 Hz, 1H), 3.75 (s, 2H), 3.48 (s, 2H), 2.71 (dd, J = 16.1, 4.2 Hz,2H), 2.24 (d, J = 15.6 Hz, 2H), 2.19 – 2.11 (m, 2H), 1.66 (d, J = 8.0 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 209.6, 162.3 (d, J=247.3 Hz), 141.1 (d, J=7.2Hz), 133.62 (d, J = 7.9 Hz), 117.5 (d, J=3.1 Hz), 116.8 (d, J = 24.0 Hz), 115.5 (d, J = 22.8 Hz), 59.4, 54.9, 48.6, 28.0.

[0123] The structural formula of the byproduct N-(2-bromo-5-fluorobenzyl)pyrrole:

[0124] ;

[0125] Its NMR characterization data: 1 H NMR (600 MHz, CDCl3) δ 7.41 (dd, J = 8.7, 5.2 Hz, 1H), 6.77 (td, J = 8.3, 3.0 Hz, 1H), 6.62 (t, J = 2.1 Hz, 2H), 6.25 (dd, J =9.3, 3.0 Hz, 1H), 6.16 (t, J = 2.1 Hz, 2H), 5.02 (s, 2H); 13 C NMR (151 MHz, CDCl3) δ 162.5 (d, J=247.6 Hz), 140.2 (d, J=7.6 Hz), 133.7 (d, J=9.1 Hz), 121.3, 116.2 (d, J=22.7 Hz), 115.8 (d, J=3.0 Hz), 115.4 (d, J=24.1Hz), 109.2,53.1.

[0126] Example 4

[0127] Example 4 provides a method for synthesizing 8-(benzo[d][3,4]dioxonylbenzyl)-8-azabicyclo[3.2.1]octane-3-one, comprising: adding 0.5 mmol tropine and 114 mg (0.6 mmol) TsOH to a dry Schlenk reaction tube, then adding 2.0 mL of 95% ethanol to the dry Schlenk reaction tube, and finally adding 76 mg (0.5 mmol) benzo[d][3,4]dioxonylbenzylamine. After mixing, the mixture is heated under air atmosphere and refluxed in an oil bath at 80°C for 10 h, after which the reaction is stopped. After the reaction is completed, the reaction system is quenched with water, and then extracted with ethyl acetate to separate the organic phase. The organic phase is dried with anhydrous Na2SO4 to remove the organic solvent, and then purified by column chromatography (silica gel column, eluent is petroleum ether and ethyl acetate in a volume ratio of 5:1) to obtain 46.7 mg of pure 8-(benzo[d][3,4]dioxonylbenzyl)-8-azabicyclo[3.2.1]octane-3-one was obtained in a brown oily form, with a calculated yield of 36%; 23.1 mg of N-(benzo[d][3,4]dioxonylbenzyl)pyrrole was obtained as an orange-yellow oily liquid byproduct, with a calculated yield of 23%.

[0128] After characterizing the 8-(benzo[d][3,4]dioxonylbenzyl)-8-azabicyclo[3.2.1]octane-3-one prepared in Example 4 by 1H NMR and 1C NMR, the results are as follows: Figure 14 and Figure 15 As shown; and the byproduct N-(benzo[d][3,4]dioxonylbenzyl)pyrrole was characterized by 1H NMR and 1C NMR, respectively, as shown in the figures. Figure 16 and Figure 17 As shown.

[0129] The structural formula of 8-(benzo[d][3,4]dioxonylbenzyl)-8-azabicyclo[3.2.1]octane-3-one:

[0130] ;

[0131] Its NMR characterization data: 1H NMR (400 MHz, CDCl3) δ 6.96 (s, 1H), 6.78 (d, J =7.9 Hz, 1H), 6.73 (d, J = 7.9 Hz, 1H), 5.92 (s, 2H), 3.62 (s, 2H), 3.45 (s,2H), 2.64 (dd, J = 16.0, 4.0 Hz, 2H), 2.17 (d, J = 15.6 Hz, 2H), 2.06 (dd, J= 7.4, 3.0 Hz, 2H), 1.59 (d, J = 7.9 Hz, 2H); 13 C NMR (101 MHz, CDCl3) δ 210.3, 147.7, 146.6, 133.2, 121.3, 108.8, 107.8, 100.8, 58.3, 54.8, 48.2, 27.7.

[0132] The structural formula of the byproduct N-(benzo[d][3,4]dioxonylbenzyl)pyrrole:

[0133] ;

[0134] Its NMR characterization data: 1 H NMR (600 MHz, CDCl3) δ 6.78 (d, J = 7.9 Hz, 1H), 6.70 (t, J = 2.0 Hz, 2H), 6.67 – 6.62 (m, 2H), 6.21 (t, J = 2.1 Hz, 2H), 5.95(s, 2H), 4.98 (s, 2H); 13 C NMR (151 MHz, CDCl3) δ 148.0, 147.1, 131.9, 120.9, 120.5, 108.5, 108.2, 107.7, 101.0, 53.1.

[0135] Example 5

[0136] Example 5 provides a method for synthesizing 8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-one, comprising: adding 0.5 mmol tropine and 114 mg (0.6 mmol) TsOH to a dry Schlenk reaction tube, then adding 2.0 mL of 95% ethanol to the dry Schlenk reaction tube, and finally adding 68 mg (0.5 mmol) 2-thiophenebenzylamine. After mixing, the mixture is heated under reflux in an oil bath at 80°C for 10 h in air, and then the reaction is stopped. After the reaction is completed, the reaction system is quenched with water, and then extracted with ethyl acetate to separate the organic phase. The organic phase is dried with anhydrous Na2SO4 to remove the organic solvent, and then purified by column chromatography (silica gel column, eluent is petroleum ether and ethyl acetate in a volume ratio of 5:1) to obtain 46.5 The pure 8-(thiophen-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-one was present as an orange-yellow oil with a calculated yield of 42%; the yield of N-(thiophen-2-ylmethyl)pyrrole was less than 5%.

[0137] After characterizing the 8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-one prepared in Example 5 by 1H NMR and 1C NMR, the results are as follows: Figure 18 and Figure 19 As shown.

[0138] The structural formula of 8-(thiophene-2-ylmethyl)-8-azabicyclo[3.2.1]octane-3-one:

[0139] ;

[0140] Its NMR characterization data: 1 H NMR (400 MHz, CDCl3) δ 7.21 (dd, J = 4.4, 2.0 Hz,1H), 6.93 – 6.90 (m, 2H), 3.88 (s, 2H), 3.52 (s, 2H), 2.66 (dd, J = 16.0, 3.6Hz, 2H), 2.18 (d, J = 16.4 Hz, 2H), 2.13 – 1.99 (m, 2H), 1.60 (q, J = 6.8 Hz, 2H); 13 C NMR (101 MHz, CDCl3) δ 209.8, 143.5, 126.2, 124.7, 124.5, 58.4, 50.3, 48.3, 27.4.

[0141] Example 6

[0142] Example 6 provides a method for synthesizing 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one, comprising: adding 0.5 mmol of 9-methyl-9-azabicyclo[3.3.1]nonane-3-one and 114 mg (0.6 mmol) TsOH to a dry Schlenk reaction tube, then adding 2.0 mL of 95% ethanol to the dry Schlenk reaction tube, and finally adding 65 mg (0.5 mmol) of benzylamine. After mixing, the mixture is heated under air atmosphere and refluxed in an oil bath at 80°C for 10 h, after which the reaction is stopped. After the reaction is completed, water is added to quench the reaction system, and the organic phase is extracted with ethyl acetate and separated. The organic phase is dried with anhydrous Na2SO4 to remove the organic solvent, and then purified by column chromatography (silica gel column, eluent is petroleum ether and ethyl acetate in a volume ratio of 5:1) to obtain 43.6 mmol / L. mg of pure 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one as a pale yellow solid, calculated yield 40%.

[0143] After characterizing the 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one prepared in Example 6 by 1H NMR and 1C NMR, the results are as follows: Figure 20 and Figure 21 As shown.

[0144] The structural formula of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one:

[0145] ;

[0146] Its NMR characterization data: 1 H NMR (600 MHz, CDCl3) δ 7.32 (d, J = 7.5 Hz, 2H), 7.25 (t, J = 7.5 Hz, 2H), 7.18 (t, J = 7.1 Hz, 1H), 3.82 (s, 2H), 3.23 (s,2H), 2.65 (dd, J = 16.4, 6.7 Hz, 2H), 2.17 (d, J = 16.2 Hz, 2H), 1.87 (td, J= 12.6, 6.3 Hz, 2H), 1.50 – 1.39 (m, 4H); 13 C NMR (151 MHz, CDCl3) δ 211.5, 139.3, 128.4, 128.3, 127.2, 57.1, 53.6, 42.9, 29.4, 16.6.

[0147] Example 7

[0148] The difference between Example 7 and Example 6 is that 0.5 mmol benzylamine was replaced with 0.5 mmol cyclopropylamine. The rest of the operation was the same as in Example 6, and 34.1 mg of pure N-substituted tropinone derivative 9-cyclopropyl-9-azabicyclo[3.3.1]nonane-3-one, a dark yellow oil, was obtained with a calculated yield of 38%.

[0149] The structural formula of 9-cyclopropyl-9-azabicyclo[3.3.1]nonane-3-one is:

[0150] ;

[0151] Its NMR characterization data: 1 H NMR (600 MHz, CDCl3) δ 3.44 (s, 2H), 2.72 (dd, J =16.4, 6.7 Hz, 2H), 2.30 (tt, J = 6.1, 3.0 Hz, 1H), 2.25 (d, J = 16.6 Hz, 2H), 1.84 (dt, J = 18.2, 9.0 Hz, 2H), 1.54 – 1.44 (m, 4H), 0.52 – 0.48 (m, 2H), 0.44 – 0.41 (m, 2H); 13 C NMR (151 MHz, CDCl3) δ 211.7, 54.5, 43.3, 33.0, 29.9,16.6, 7.0.

[0152] Example 8

[0153] The difference between Example 8 and Example 1 is that 0.5 mmol benzylamine was replaced with 0.5 mmol p-chlorobenzylamine. The rest of the operation was the same as in Example 1. 43.7 mg of pure N-substituted tropinone derivative 8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-one was obtained as an orange oil, with a calculated yield of 35%. 20.1 mg of N-(4-chlorobenzyl)pyrrole as a byproduct was also obtained as a brown oil, with a calculated yield of 21%.

[0154] The structural formula of 8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octane-3-one is:

[0155] ;

[0156] Its NMR characterization data: 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 7.7 Hz, 2H), 3.66 (s, 2H), 3.41 (s, 2H), 2.62 (d, J = 15.7 Hz, 2H), 2.16 (d, J = 15.9 Hz, 2H), 2.09 – 2.01 (m, 2H), 1.59 (d, J = 7.9 Hz, 2H); 13 C NMR (101 MHz, CDCl3) δ 209.9, 137.8, 132.6, 129.6, 128.4, 58.5, 54.4, 48.2, 27.7.

[0157] The structural formula of the byproduct N-(4-chlorobenzyl)pyrrole is:

[0158] ;

[0159] Its NMR characterization data: 1 H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 6.69 (t, J = 2.0 Hz, 2H), 6.22 (t, J = 2.1 Hz, 2H), 5.05 (s, 2H); 13 C NMR (151 MHz, CDCl3) δ 136.7, 133.5, 128.8, 128.3, 121.0,108.8, 52.6.

[0160] Example 9

[0161] The difference between Example 9 and Example 1 is that 0.5 mmol benzylamine was replaced with 0.5 mmol p-methoxybenzylamine. The rest of the operation was the same as in Example 1. 54.0 mg of pure N-substituted tropinone derivative 8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octane-3-one was obtained as a brown oil, with a calculated yield of 44%; 28.1 mg of N-(4-methoxybenzyl)pyrrole as a dark brown oily byproduct was also obtained, with a calculated yield of 30%.

[0162] The structural formula of 8-(4-methoxybenzyl)-8-azabicyclo[3.2.1]octane-3-one is:

[0163] ;

[0164] Its NMR characterization data: 1 H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 3.80 (s, 3H), 3.67 (s, 2H), 3.47 (s, 2H), 2.67 (d,J = 15.3 Hz, 2H), 2.19 (d, J = 15.9 Hz, 2H), 2.12 – 2.06 (m, 2H), 1.61 (d, J= 7.9 Hz, 2H); 13 C NMR (101 MHz, CDCl3) δ 210.4, 158.7, 131.3, 129.5, 113.7, 58.3, 55.2, 54.4, 48.2, 27.7.

[0165] The structural formula of the byproduct N-(4-methoxybenzyl)pyrrole:

[0166] ;

[0167] Its NMR characterization data: 1 H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.56 Hz, 2H), 6.94 (d, J = 8.61 Hz, 2H), 6.76 (t, J = 1.96 Hz, 2H), 6.26 (t, J = 1.98 Hz, 2H), 5.07 (s, 2H), 3.86 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 159.2, 130.2, 128.5, 121.0, 114.2, 108.5, 55.3, 52.9. Methoxy MeO is the organic functional group "-OCH3".

[0168] Example 10

[0169] The difference between Example 10 and Example 1 is that 0.5 mmol of benzylamine was replaced with 0.5 mmol of 2,4,6-trifluorobenzylamine. The rest of the operation was the same as in Example 1. 52.5 mg of pure N-substituted tropinone derivative 8-(2,4,6-trifluorobenzyl)-8-azabicyclo[3.2.1]octane-3-one was obtained as a brown solid, with a calculated yield of 39%; 24.2 mg of N-(2,4,6-trifluorobenzyl)pyrrole as a white solid was also obtained, with a calculated yield of 30%.

[0170] The structural formula of 8-(2,4,6-trifluorobenzyl)-8-azabicyclo[3.2.1]octane-3-one is:

[0171] ;

[0172] Its NMR characterization data: 1 H NMR (600 MHz, CDCl3) δ 6.66 (t, J = 8.2 Hz, 2H), 3.72 (s, 2H), 3.50 (s, 2H), 2.66 (dd, J = 16.0, 3.9 Hz, 2H), 2.19 (d, J =15.7 Hz, 2H), 2.13 – 2.06 (m, 2H), 1.61 (d, J = 7.9 Hz, 2H); 13 C NMR (151MHz, CDCl3) δ 209.7, 163.1 – 162.7 (m), 161.40– 161.0 (m), 111.6 (td, J =19.6, 4.4 Hz), 100.1 (td, J = 25.2, 6.8 Hz), 59.1, 48.2, 42.0, 27.8.

[0173] The structural formula of the byproduct N-(2,4,6-trifluorobenzyl)pyrrole:

[0174] ;

[0175] Its NMR characterization data: 1 H NMR (600 MHz, CDCl3) δ 6.81 (s, 2H), 6.73 (t, J =8.1 Hz, 2H), 6.28 – 6.13 (m, 2H), 5.12 (s, 2H); 13 C NMR (151 MHz, CDCl3) δ162.6 (dt, J=250.6, 15.1Hz), 161.6 (dq, J=250.7, 15.1, 4.5Hz), 120.7, 110.3(td, J = 20.1, 4.8 Hz), 108.6, 100.5 (td, J = 25.7, 6.0 Hz), 39.8.

[0176] Example 11

[0177] The difference between Example 11 and Example 1 is that 0.5 mmol of benzylamine was replaced with 0.5 mmol of 2-pyridinemethylamine. The rest of the operation was the same as in Example 1. 46.5 mg of pure N-substituted tropinone derivative 8-(pyridin-2-methyl)-8-azabicyclo[3.2.1]octane-3-one, a brown oily substance, was obtained with a calculated yield of 43%; 19.0 mg of the byproduct 2-(pyrrole-1-methyl)pyridine, a brown oily substance, was obtained with a calculated yield of 24%.

[0178] The structural formula of 8-(pyridin-2-methyl)-8-azabicyclo[3.2.1]octane-3-one:

[0179] ;

[0180] Its NMR characterization data: 1 H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 4.9 Hz, 1H),7.72 – 7.64 (m, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.21 – 7.12 (m, 1H), 3.89 (s,2H), 3.51 (s, 2H), 2.73 (dd, J = 16.0, 4.2 Hz, 2H), 2.21 (d, J = 15.8 Hz, 2H), 2.17 – 2.11 (m, 2H), 1.63 (d, J = 8.0 Hz, 2H); 13 C NMR (101 MHz, CDCl3) δ210.0, 159.4, 149.1, 136.6, 122.5, 122.1, 59.0, 57.1, 48.1, 27.8.

[0181] The structural formula of the byproduct 2-(pyrrole-1-methyl)pyridine is:

[0182] ;

[0183] Its NMR characterization data: 1H NMR (600 MHz, CDCl3) δ 8.56 (d, J = 4.3 Hz, 1H), 7.61 (td, J = 7.7, 1.8 Hz, 1H), 7.18 (dd, J = 7.4, 4.9 Hz, 1H), 6.80 (d, J =7.9 Hz, 1H), 6.74 (t, J = 2.1 Hz, 2H), 6.22 (t, J = 2.1 Hz, 2H), 5.21 (s, 2H); 13 C NMR (151 MHz, CDCl3) δ 158.3, 149.2, 137.2, 122.4, 121.4, 120.8,108.9, 55.1.

[0184] Example 12

[0185] The difference between Example 12 and Example 1 is that 0.5 mmol of benzylamine was replaced with 0.5 mmol of 3-pyridinemethylamine. The rest of the operation was the same as in Example 1, and 44.3 mg of pure N-substituted tropinone derivative 8-(pyridin-3-methyl)-8-azabicyclo[3.2.1]octane-3-one was obtained as an orange-yellow oil, with a calculated yield of 41%; 25.2 mg of brown oily byproduct 3-(pyrrole-1-methyl)pyridine was obtained, with a calculated yield of 32%.

[0186] The structural formula of 8-(pyridin-3-methyl)-8-azabicyclo[3.2.1]octane-3-one is:

[0187] ;

[0188] Its NMR characterization data: 1 H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.48 – 8.43 (m,1H), 7.75 – 7.69 (m, 1H), 7.23 (dd, J = 7.6, 5.0 Hz, 1H), 3.69 (s, 2H), 3.41(s, 2H), 2.65 – 2.55 (m, 2H), 2.19 – 2.11 (m, 2H), 2.06 (dd, J = 7.6, 3.8 Hz, 2H), 1.58 (d, J = 8.1 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 209.7, 149.7, 148.5, 136.2, 134.7, 123.4, 58.6, 52.7, 48.2, 27.7.

[0189] The structural formula of the byproduct 3-(pyrrole-1-methyl)pyridine is:

[0190] ;

[0191] Its NMR characterization data: 1 H NMR (600 MHz, CDCl3) δ 8.53 (dd, J = 4.7, 1.3 Hz,1H), 8.47 (d, J = 1.7 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.24 (dd, J = 7.8,4.8 Hz, 1H), 6.68 (t, J = 2.1 Hz, 2H), 6.21 (t, J = 2.1 Hz, 2H), 5.08 (s, 2H); 13 C NMR (151 MHz, CDCl3) δ 149.1, 148.4, 134.6, 133.7, 123.6, 120.9,109.0, 50.7.

[0192] Example 13

[0193] The difference between Example 13 and Example 1 is that 0.5 mmol benzylamine was replaced with 0.5 mmol n-butylamine. The rest of the operation was the same as in Example 1, and 33.5 mg of yellow oily product 8-butyl-8-azabicyclo[3.2.1]octane-3-one was obtained, with a calculated yield of 37%.

[0194] The structural formula of 8-butyl-8-azabicyclo[3.2.1]octane-3-one is:

[0195] ;

[0196] Its NMR characterization data: 1H NMR (600 MHz, CDCl3) δ 3.53 (s, 2H), 2.65 (dd, J =15.9, 3.6 Hz, 2H), 2.60 – 2.54 (m, 2H), 2.20 – 2.13 (m, 2H), 2.06 – 1.99 (m,2H), 1.60 – 1.49 (m, 4H), 1.39 (q, J = 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13 C NMR (151 MHz, CDCl3) δ 210.1, 58.5, 49.9, 47.2, 31.2, 27.9, 20.7, 14.0.

[0197] Example 14

[0198] Example 14 provides a gram-scale synthesis method for Example 1. The specific steps include: adding 10 mmol of tropinone and 2.28 g (12 mmol) of TsOH to a 100 mL three-necked flask, then adding 40 mL of 95% ethanol to the three-necked flask, and finally adding 1.3 mL of benzylamine. The mixture is then heated under air atmosphere and refluxed in an oil bath at 80 °C for 10 h before stopping the reaction. After the reaction is complete, water is added to quench the reaction system, and then ethyl acetate is used for extraction to separate the organic phase. The organic phase is dried with anhydrous Na2SO4 to remove the organic solvent, and then purified by column chromatography (silica gel column, eluent is petroleum ether and ethyl acetate in a volume ratio of 5:1) to obtain 1.03 g of pure N-substituted tropinone as a pale yellow oily liquid, with a calculated yield of 48%.

[0199] Specifically, the fatty amine derivatives involved in the reaction, the target products and by-products of the reaction, and their yields in Examples 1 to 13 are shown in Table 1.

[0200] Table 1 Reactants, reaction products and their yields in Examples 1 to 13

[0201]

[0202] While the embodiments of the present invention have been described above, it should be understood that modifications and variations can be made to these embodiments by those skilled in the art, and all such modifications and variations fall within the scope of the present invention as described in the claims.

Claims

1. A kind N -A method for synthesizing substituted tropinone derivatives, characterized in that, include: In a solvent environment, under the action of an acid accelerator, tropinone compound I reacts with fatty amine derivative II in one step to form... N -Substituted tropinone derivative III, the reaction temperature is 70℃-90℃; ； Where m is independently selected from the natural numbers 1 to 2; The fatty amine derivative II is selected from benzylamine, p-methylbenzylamine, 2-bromo-5-fluorobenzylamine, benzo[ d [3,4] One of dioxanebenzylamine, 2-thiophenebenzylamine, cyclopropylamine, p-chlorobenzylamine, p-methoxybenzylamine, 2,4,6-trifluorobenzylamine, 2-pyridinemethylamine, 3-pyridinemethylamine, and n-butylamine; wherein the acid accelerator is p-toluenesulfonic acid.

2. The synthesis method according to claim 1, characterized in that, The solvent is selected from at least one of ethanol, toluene, DMF, DME, DMSO, acetonitrile, and ethylene glycol.

3. The synthesis method according to claim 1, characterized in that, The molar ratio of the acid promoter to tropinone compound I is (1-2):1; and / or, the molar ratio of the fatty amine derivative II to tropinone compound I is (1-2):1; and / or, the solvent dosage is 1 mL to 5 mL of solvent added for every 0.5 mmol of tropinone compound.

4. The synthesis method according to claim 1, characterized in that, The reaction lasted for 8-12 hours.

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